Synthesis of optically active leukotriene (SRS-A) intermediates

Tetrahedron LetL,ers Vol. 21, pp 4163 - 4166 @pergamon Press Lta. 198C. Printed In Great

SYNTHESIS

OF OPTICALLY (SRS-A)

Noal Cohen*, Chemical

Bruce L

Research

In an approach

Its

B-eplmer

tartrate, Intensive reacting

recent

(SRS's)

unstable,

spasmogenic

enzymatic

transformations

structural

atom at C-6 as well derive.

phillc whose

attack parent

(-)-(5&@)-

efforts

(5S_,6S)-epoxy alcohol

9 and

acid and &-dlethyl

upon

acid 1s also

the presumed

envIsIoned epoxy

to form 2

acid

Wittig

These

ester synthon Herein,

precursor

would

be united

has already

gave the unsaturated

4163

ester

nucleoester

pure

or thirteen-carbon of the

Into LTC.+ by Corey

and

18 1s presented. and readily

modifications from

(L),

' an optically

to construction

derived

bromide g (n-BuLl,THF,-30°C-R.T.) R.T.)

In which

(cls-epoxide)

the phosphorane

and instrumental

In LTA4 methyl

from inexpensive

acrd) by stralghtforward

their

regioselectlve

with an eleven-

of the C-6 epimer

of 2 with

forthcomIng

been converted

via a sulfur

from which

to the SRS's

our approach

and synthetically

acid residues

all Involve

choral approach

we describe

arIse via antigen-trig-

chromophore been

of "slow

condltlons. 1

lntrlgulng

epoxlde moiety

(?I4 was prepared

(erythorbic

condensation

approaches

biogenetic

a synthesrs

pyridine,

of amino

the allyllc

a convergent,

epoxy ester 2 which

In addltlon,

leukotrlenes,'

trlene

of a family

anaphylactrc

acid and possess

In this area have already

nucleophlles

chloride,

the key

and related

conlugated

of sulfur

yl)ethyl]trlphenylphosphonlum (benzoyl

Inc ,

from g-araboascorbic

such as the attachment

3b

able -D-araboascorblc 5

Roche

07110

thereof,

(1 a-c), named

of arachldonic

2,3-O-IsopropylIdene-D-erythrose

procedures

Hoffmann-La

In asthma

conflrmatlon

hydroxy

co-workers.3b

compounds

features

Synthetic

fragment

J. Lopresti

have led to the characterlzatlon

structural

or nine-carbon

oleflnic

and Rocco

New Jersey

as the characterlstlc

We, as others,3b seven-

Banner,

starting

implicated

gered

in providing

prepared

lnvestlgatlons

These

names

INTERMEDIATES

to SRS-A and analogues

-18 were

LEUKOTRIENE

respectively

substances"

challenging

ACTIVE

Department,

Nutley,

Summary.

oooo-4039/80/1032-4163$0?.0c1/0 Britain

avall-

of known

[2-(1,3-dloxan-2-

followed by benzoylation 10 acetal2 (oll,[a]=D +48.7'

4154

IO , R'=r-Glu,R2

= Gly ( LTCq )

b , R’ = I-I , R2 = Gly C,

-

R’ =H

, R*=OH

( LT&

)

ILTEI)

-

p&co2CHa

n-C5“I,

2

5 , R --“cc

(LTA4

methyl

ester

1

7 ,R=H

3

0

6, R= -!O(CHz)30H

R’ 01’ 10,

H

H

R’ =;,

8 , R- so2ctix

y/H H

R2

I~,R=H

R2=CH20H

17 , R= S02CH3

11 , R’=$R2=CH$H 12 , R’ = :Ph ,R2. CHO 0 13, R’ = !Ph ,R2=L-CH=CHCH2C~ ‘0

t

P

14,

R’=CPh,R2=KH213C,~

15,

0 9O R’=~Ph,R2=Ui2)JCO(CH2)~OH

3

H

0

,H

HO&4q/-.402CH3 I8

(c l,CHCIJ))

in 60% yield

quantltatlvely dlester

afforded

(oll;[al’“D

6 lo

at -7*0&12

Latalytlc

+11.5’(~

In a crucial

trrfluoroacetrc

+15.2'(c

1,CHCl,))

when

transformation,

ester

yield

In this process,

exposed

drester

selectively

the hydroxyl

liberating

of -7 was sluggish, 13 standard condltlons.

functions

which

ethyl acetate,

smoothly

to excess

acetonrde

ozone,

6, upon

provided

the

III ethyl acetate,

treatment

with

the correspondrng

under

Treatment

carbonate

in methanol

epoxlde -9 3b (orl,[a]'"D

-35'(c

at C-5 and C-6 are drfferentlated

the C-6 OH for conversIon

tosylatlon

potassium

of 5 over platlnum,ln

1,CHCla))

9 1

acid-water, (0°C,NaHC03quench), gave the beautifully crystallrne erythro10 lactone _ 7 (mp 90 5-91 5'C from ether, [a]'"D l34 8O(c 1,CHC13)) in 70%

hydroxy

formatIon

hydrogenatron

2 '" (o=l,[ele'D

Into a leaving

orly mesylate

of -8 with

(1 1 equlv K~CO 3,0-5'C,70%

group.

8 was formed

sodium methoxlde yreld)

by lactone Whereas,

quantltatlvely

or, preferably,

anhydrous

led to the trans-(55,62)-

0 2,CHCl&14

Treatment sequence was employed for synthesis of the -cls-(55,6R)-epoxide 18 _ 15 10 10 wrth one cqu*v of benzoyl chloride in pyrrdine gave the monoester 11 -

A slmrlar

of the trans-dlol (oll,[alZ5D which

-7.5='(c l,CHC13))

could be removed

(oil,[alz3D

+17.1°(c

In 45-50%

by chromatography

2,CHClz))

which,

4, gave the eplmer -131° (oll,[alZ'D Catalytrc

hydrogenation

then provided transformed

drester

furnlshed

’

epoxide -18

and recycled

vra

the Wlttlg

-32 8'(c

15 lo (a&[a]e5D

[a12'D +30

along with

dlester

and stnrtlng dial both of 16 10 of 11 gave aldehyde -12 Oxidation

procedure

l,CHCl,))

-14 lo (o~l;[d]'~D

-15 Into the crystalline

ethyl acet;;e;;ther,

yreld

In 45% overall

ester

7' (c l,CHCl?)),

(o~~,[cx]~~II i-2 l'(c 0.5,CHCl,))

above

yield

for preparing

from

-16 2O(c 2,CHC1,1)} and ozone

-13 9'(c Z,CHC&)) threo-hydroxy

descrrbed

Aqueous

trlfluoroacetlc

lactone -16 lo (mp 104 5-106'C

the mesylate when

11 oxldatlon

exposed

(17) of whrch to potassium

ylelded

carbonate

11

acid from (70%) II-I

methanol. Having currently

the optically

preparing

of these studies

Acknowledgements Dr

Gabriel

provided certain

active

a varrety

synthons

will be publrshed

We are grateful

Saucy during

vra the above

for pharmacological

schemes,

evaluation

we are

The results

in due course.

for the support

the course

by Dr. John W. Scott and Mr lntermedlates

-9 and -18 available

of SRS analogs

of this work Gary Srwruk

and encouragement

provided

by

The assistance regarding

the large scale preparatr_on of

must also be mentIoned

References la.

R C Murphy, S. Hammarstrom, and B Samuelsson, Proc Nat1 Acad Sci U.S.A , 76, 4275 (1979), (b) S. Hammarstrom, R C Murphy, B Samuelsson, D.A Clark, C. Mroskowskl, and E.J. Corey, Blochem Blophys. Res. Commun , 91, 1266 (1979), (c) S Hanunarstrom, B Samuelsson, D.A Clark, G Goto, A. Marfat, C Mloskowskr, and E.J. Corey, rbrd., 92, 946 (1980), (d) 0 Radmark, C. Malmsten, B. Samuelsson, D.A Clark, G Goto, A. Marfat, and E.J. Corey, rbld , 92, 954 (1980), (e) M.K. Bach, J R Brashler, S. Hammarstrom, and B. Samuelsson, rbld , 93, 1121 (1980), (f) H R Morrrs, G W Taylor, P.J Piper, M N. Samhoun, and J R TIppIns, Prostaglandlns, 19, 185 (1980), Natl. Acad Scl U S A , 7J, (g) L Ornmg, S Hammarstrom, and & Samuelsson, Proc

4166

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3a.

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, 3.

11,

785

4.

C.E

5.

D-Araboascorblc acrd was treated wrth dlazotlzed p-toluldlne (NaNOz/aqueous HzS04) at ?C glvrng (-)-(3R-cls)-mono(tetrahy~ro-4-hydroxy-2-oxo-3-furanyl)ester 2-(4-methyl-~ phenyl)hydrazlde of ethanedlolc acid6 (55%, mp 187-9OC d r[a]25D -59.3'(c O.S,EtOH)), which,when hydrolyzed III bolllng water,afforded D-erythronolactone6 (74%, mp 97.5999C,[c]25D -71 4'(c 0 5,HzO)) The acetonrde7,z was then prepared (2,2-drmethoxypropane-acetone-p-T&H, 77%, mp 66-68", [alF5D -122.0°(c l,HzO)) whach was reduced with This DIBAH m CHeClz, at -780~,8 grvrng 3, [cL]-~D -76"(c l,CHCls), In 90% yield sequence was easrly carried out on 100-200 g scale

6.

R. Werdenhagen

and H. Wegner,

/.

D.L

Mrtchell,

Can. J

8.

R.E

Ireland,

9

J-C

Stowell

Ballou,

J

Am

C S

Chem

Sot

Chem. Ber

z,

2010

(1939).

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Chem

Wrlcox,

165 (1957)

and S

and D R. Kerth,

Thalsrzvongs,

Synthesis,

J

Org

Chem

, 43, 786 (1978).

132 (1979)

IO

This compound provrded compatrble (50.3%) C,H mlcroanalysls.

11.

P. Deslongchamps, 3651 (1974).

12.

Attempted direct lntroductlon of the carboxyethyl morety by a Wittlg reactron of 2 with the phosphorane from (Z-carboxyethyL)trlphenylphosphonlum chloride (H S Corey, Sot , a, 1884 (1964)) was Jr., J R D. McCormrck, and W E. Swensen, J Am Chem unsuccessful.

13.

R.K

14,

2.91 'H NMR (CDCls,lOOMHz) 6 3 66(s,3, CO&Hz), 3 59, 3 86 (2m,2, -Cg20H), (t,l, J=GHz,OH-exchanged epoxrde CH), 2 37 (t,Z, J=6 SHz, CI&COzCH3), 2.19 1.69 ppm (m,4,(CH2)2)

Crossland

P. Atlanr,

IR, NMR,

D. Frghel,

and K.L. Servrs,

A

and mass

spectral

Malaval,

and C

J. Org. Chem

, 35,

3195

data and a satrsfactory

Moreau,

Can

J. Chem

, 52,

(1970)

15.

Readily available from k-(+)-dlethyl tartrate- B A. Murrer, P.N NIcholson, and D. Parker, Synthesm, 350 (1979)

J.M. Brown,

16

A.J

2480

17.

6 3 74 (m,2,C&OH), 3 67(s,3,COzCHs), 3.14. 3 00 (2 d of t, 'H NMR (CDCla, 100 MHZ) 1 7OPPm 2, Jv1c=4Hz, epoxrde CH), 2 54(m,l,OH), 2 39 (t,2, J=6 5Hz, C&COeCH3),

Mancuso,

S.-L

Huang,

and D. Swern,

(m, 4,(CHs)z) (Received

In USA

II July

1980)

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Org

Chem., 43,

P A

(m,z,

with D&O),

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(1978)